The present invention relates to compounds having biological activity, to pharmaceutical compositions containing the compounds, and to a medical method of treatment.
More particularly, the present invention concerns certain 1,2diamino-4,5-dimethoxycyclohexane amide derivatives have analgesic activity, to pharmaceutical compositions containing these compounds, and to a method of alleviating pain in mammals by administering the pharmaceutical compositions.
The search for strong analgesics which also possess minimal potential for dependency has been among the highest priority efforts in pharmaceutical research. These research efforts have, to a great extent, involved chemical modification of the opiate structure and the discovery of novel compounds which possess morphine-like activity.
The discovery of endogenous opioids has led workers in the field to consider that these peptides, possessing less rigid structures, might interact with opioid receptors other than those which the classical rigid structure opiates, such as morphine, bind.
The concept of multiple opioid receptors has been supported by studies with nalorphine and a series of benzomorphans which display unusual pharmacological properties dissimilar from morphine, yet blocked by the selective opioid antagonists. [See, for example, W. R. Martin, et al, J. Pharmacol. Exp. Ther., 197: 517-532 (1976). ]
The existence of multiple types of opioid receptors is of importance because it suggests the possibility of separating the desirable analgesic and psychotherapeutic effects of a drug compound from the undesirable abuse potential or habituating effects.
U.S. Pat. No. 4,098,904 discloses certain cis- and trans-N-(2-aminocycloaliphatic)benzamide compounds having analgesic activity.
U.S. Pat. No. 4,145,435 describes certain 2-amino-cycloaliphatic amide compounds as analgesics. In particular, trans-3,4-dichloro-N-[2-pyrrolidinyl)-cyclohexyl]benzacetamide is reported to possess selective kappa agonist activity, and therefor to possess analgesic activity without attendant dependence liability. [See P. V. Vonvoigtlander, et al., J. Pharmacol. Exp. Ther., 224: 7-12 (1983).]
U.S. Pat No. 4,212,878 discloses certain N-[(4-mono- or di-oxygen-group-substituted-1-amino-cyclohex-1-yl)methyl)phenylacetamides, particularly 2-(3,4dichlorophenyl)-N[[8-(1pyrrolidinyl)-1,4-diaxaspiro[4.5]dec-8-yl]met hyl]acetamide having analgesic properties.
U.S. Pat. No. 4,359,476 discloses certain N-[2-amino(oxy or thio group) substituted cycloaliphatic]phenylacetamide and -benzamide compounds having the oxy- or thio group substituents on a cycloaliphatic ring carbon adjacent to either of the nitrogen-bearing carbon atoms of the cycloaliphatic ring. These compounds, having analgesic activity are typified by cis- and trans-4-bromo-N-[3-methoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methylbenzamide .
U.S. Pat. No. 4,598,087 and its divisional, U.S. Pat. No. 4,677,122, disclose certain oxy- or thioacetamides of trans-1,2-diaminocyclohexane having analgesic activity. These compounds are typified by trans-2-(2,3-dichlorophenoxy)-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]ace tamide.
U.S. Pat. No. 4,656,182 discloses certain trans-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzo[b]thiophene acetamides having analgesic activity.
U.S. Pat. No. 4,663,343 discloses certain trans-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-naphthalenyloxy-and naphthalenylthioacetamides having analgesic activity.